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This is a phase II randomized study of 4-months induction first-line chemotherapy with FOLFOXIRI + cetuximab followed by maintenance with cetuximab or bevacizumab in patients affected by KRAS wild type (wt) mCRC.

10m-PFR is defined as the proportion of patients free from disease progression 10 months after randomization, relative to the total of enrolled patients. Patients whose disease status cannot be evaluated within 11 months after randomization and patients lost to follow up or dead within 10 months after randomization will be considered as progressed for the purpose of the primary endpoint analyses.

Secondary Outcome Measures :

Best overall response rate [ Time Frame: every 8 weeks, up to 60 months ]

Best overall response rate is defined as the percentage of patients, relative to the total of enrolled subjects, achieving a complete (CR) or partial (PR) response, according to RECIST 1.1 criteria, during the induction and the maintenance phases of treatment. The determination of clinical response will be based on investigator reported measurements that will be subsequently confirmed by a central review. Responses will be evaluated every 8 weeks until disease progression or up to 60 months. Patients who do not have an on-study assessment will be included in the analysis as non responders.

10month resection rate is defined as the percentage of patients,relative to the total of enrolled subjects,undergoing secondary R0 resection of metastases within 10months after randomization.Secondary R0 surgery is defined as microscopically margin free complete surgical removal of all residual disease,performed during treatment or after its completion,allowed by tumoral shrinkage and/or disappearance of 1or more lesions.Patients lost to follow up,with disease progression or dead,within 10months after randomization,will be considered as failures.

Time to strategy failure [ Time Frame: from randomization, up to 60 months ]

It is defined as the time from randomization to one of the followings:

progression during FOLFOXIRI + cetuximab or during a modified FOLFOXIRI + cetuximab regimen;OR

progression and decision to not administer FOLFOXIRI + cetuximab or a modified FOLFOXIRI + cetuximab regimen

introduction of a new agent not included in the study treatment according to randomization arm;OR

death; whichever occurs first.All events will be assessed up to 60 months.For patients still on treatment at the time of analysis, the time to strategy failure will be censored on the last date the patients were known to be alive.

Time to 2nd progressive disease [ Time Frame: from randomization, up to 60 months ]

It is defined as the time from randomization to 2°documentation of objective disease progression or death due to any cause,whichever occurs first.All events will be assessed up to 60 months.Time to 2nd progressive disease will be censored on the date of the last evaluable on study tumor assessment documenting absence of progressive disease for patients who are alive,on study and second progression free at the time of the analysis.Alive patients having no tumor assessments after baseline will have time to event endpoint censored on the date of randomization

Progression free survival (PFS) [ Time Frame: from randomization to first documentation of objective disease progression or death, up to 60 months ]

It is defined as the time from randomization to first documentation of objective disease progression or death due to any cause,whichever occurs first. All events will be assessed up to 60 months. PFS will be censored on the date of the last evaluable on study tumor assessment documenting absence of progressive disease for patients who are alive,on study and progression free at the time of the analysis.Alive patients having no tumor assessments after baseline will have time to event endpoint censored on the date of randomization

Overall survival (OS) [ Time Frame: as the time from randomization to the date of death, up to 60 months ]

It is defined as the time from randomization to the date of death due to any cause. All events will be assessed up to 60 months. For patients still alive at the time of analysis, the OS time will be censored on the last date the patients were known to be alive.

Toxicity rate [ Time Frame: during the induction and the maintenance phases of treatment ]

It is defined as the percentage of patients,relative to the total of enrolled subjects,experiencing a specific adverse event of grade 3/4,according to National Cancer Institute Common Toxicity Criteria (version 4.0),during the induction and the maintenance phases of treatment.

Overall toxicity rate [ Time Frame: during the induction and the maintenance phases of treatment ]

It is defined as the percentage of patients, relative to the total of enrolled subjects, experiencing any adverse event of grade 3/4, according to National Cancer Institute Common Toxicity Criteria (version 4.0), during the induction and the maintenance phases of treatment.

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Serious underlying medical condition (judged by the investigator) which could impair the ability of the patient to participate in the trial (e.g. uncontrolled diabetes mellitus, active autoimmune disease)

Concurrent treatment with other experimental drugs or other anti-cancer therapy; treatment in a clinical trial within 30 days prior to trial entry

Definite contraindications for the use of corticosteroids and antihistamines as premedication

Known hypersensitivity to trial drugs or hypersensitivity to any other component of the trial drugs

Any concomitant drugs contraindicated for use with the trial drugs according to the product information of the pharmaceutical companies

Pregnancy

Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial

Medical or psychological condition which, in the opinion of the investigator, would not permit the patient to complete the study or sign meaningful informed consent